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1.
Toxicol Lett ; 341: 68-79, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33548343

RESUMO

BACKGROUND: General anesthetics such as sevoflurane interfere with dendritic development and synaptogenesis, resulting in cognitive impairment. The collapsin response mediator protein2 (CRMP2) plays important roles in dendritic development and synaptic plasticity and its phosphorylation is regulated by cycline dependent kinase-5 (Cdk5) and glycogen synthase kinase-3ß (GSK-3ß). Here we investigated whether Cdk5/CRMP2 or GSK-3ß/CRMP2 pathway is involved in sevoflurane-induced developmental neurotoxicity. METHODS: Rats at postnatal day 7 (PND7) were i.p. injected with Cdk5 inhibitor roscovitine, GSK-3ß inhibitor SB415286 or saline 20 min. before exposure to 2.8% sevoflurane for 4 h. Western-blotting was applied to measure the expression of Cdk5/CRMP2 and GSK-3ß/CRMP2 pathway proteins in the hippocampus 6 h after the sevoflurane exposure. When rats grew to adolescence (from PND25), they were tested for open-field and contextual fear conditioning, and then long term potentiation (LTP) from hippocampal slices was recorded, and morphology of pyramidal neuron was examined by Golgi staining and synaptic plasticity-related proteins expression in hippocampus were measured by western-blotting. In another batch of experiment, siRNA-CRMP2 or vehicle control was injected into hippocampus on PND5. RESULTS: Sevoflurane activated Cdk5/CRMP2 and GSK-3ß/CRMP2 pathways in the hippocampus of neonatal rats, reduced dendritic length, branches and the density of dendritic spine in pyramidal neurons. It also reduced the expressions of PSD-95, drebrin and synaptophysin in hippocampus, impaired memory ability of rats and inhibited LTP in hippocampal slices. All the impairment effects by sevoflurane were attenuated by pretreatment with inhibitor of Cdk5 or GSK-3ß. Furthermore, rat transfected with siRNA-CRMP2 eliminated the neuroprotective effects of Cdk5 or GSK-3ß blocker in neurobehavioral and LTP tests. CONCLUSION: Cdk5/CRMP2 and GSK-3ß/CRMP2 pathways participate in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats.


Assuntos
Disfunção Cognitiva/induzido quimicamente , Quinase 5 Dependente de Ciclina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sevoflurano/toxicidade , Aminofenóis/farmacologia , Animais , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Dendritos/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Maleimidas/farmacologia , Proteínas do Tecido Nervoso/genética , Inibidores de Proteínas Quinases/farmacologia , Células Piramidais/efeitos dos fármacos , Ratos , Roscovitina/farmacologia
2.
Nat Commun ; 12(1): 182, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420090

RESUMO

Processing within the anterior cingulate cortex (ACC) is crucial for the patterning of appropriate behavior, and ACC dysfunction following chronic drug use is thought to play a major role in drug addiction. However, cortical pyramidal projection neurons can be subdivided into two major types (intratelencephalic (IT) and pyramidal tract (PT)), with distinct inputs and projection targets, molecular and receptor profiles, morphologies and electrophysiological properties. Yet, how each of these cell populations modulate behavior related to addiction is unknown. We demonstrate that PT neurons regulate the positive features of a drug experience whereas IT neurons regulate the negative features. These findings support a revised theory of cortical function in addiction, with distinct cells and circuits mediating reward and aversion.


Assuntos
Preparações Farmacêuticas , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Recompensa , Animais , Córtex Cerebral/fisiologia , Cocaína , Fenômenos Eletrofisiológicos , Masculino , Tratos Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley
3.
Nature ; 590(7845): 315-319, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33328636

RESUMO

Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4-6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.


Assuntos
Antidepressivos/farmacologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Fatores de Iniciação em Eucariotos/genética , Fatores de Iniciação em Eucariotos/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Ketamina/análogos & derivados , Ketamina/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Mutação , Inibição Neural/efeitos dos fármacos , Inibição Neural/genética , Neurônios/classificação , Neurônios/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Transmissão Sináptica/efeitos dos fármacos
4.
Anesthesiology ; 134(2): 219-233, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33332534

RESUMO

BACKGROUND: The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. METHODS: Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 µM propofol application. RESULTS: Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. CONCLUSIONS: These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Interneurônios/efeitos dos fármacos , Propofol/farmacologia , Células Piramidais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Feminino , Masculino , Modelos Animais , Ratos , Ratos Transgênicos , Sinapses/efeitos dos fármacos
5.
PLoS One ; 15(6): e0230465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559219

RESUMO

The slow afterhyperpolarising current, sIAHP, is a Ca2+-dependent current that plays an important role in the late phase of spike frequency adaptation. sIAHP is activated by voltage-gated Ca2+ channels, while the contribution of calcium from ryanodine-sensitive intracellular stores, released by calcium-induced calcium release (CICR), is controversial in hippocampal pyramidal neurons. Three types of ryanodine receptors (RyR1-3) are expressed in the hippocampus, with RyR3 showing a predominant expression in CA1 neurons. We investigated the specific role of CICR, and particularly of its RyR3-mediated component, in the regulation of the sIAHP amplitude and time course, and the activity-dependent potentiation of the sIAHP in rat and mouse CA1 pyramidal neurons. Here we report that enhancement of CICR by caffeine led to an increase in sIAHP amplitude, while inhibition of CICR by ryanodine caused a small, but significant reduction of sIAHP. Inhibition of ryanodine-sensitive Ca2+ stores by ryanodine or depletion by the SERCA pump inhibitor cyclopiazonic acid caused a substantial attenuation in the sIAHP activity-dependent potentiation in both rat and mouse CA1 pyramidal neurons. Neurons from mice lacking RyR3 receptors exhibited a sIAHP with features undistinguishable from wild-type neurons, which was similarly reduced by ryanodine. However, the lack of RyR3 receptors led to a faster and reduced activity-dependent potentiation of sIAHP. We conclude that ryanodine receptor-mediated CICR contributes both to the amplitude of the sIAHP at steady state and its activity-dependent potentiation in rat and mouse hippocampal pyramidal neurons. In particular, we show that RyR3 receptors play an essential and specific role in shaping the activity-dependent potentiation of the sIAHP. The modulation of activity-dependent potentiation of sIAHP by RyR3-mediated CICR contributes to plasticity of intrinsic neuronal excitability and is likely to play a critical role in higher cognitive functions, such as learning and memory.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Cálcio/metabolismo , Cálcio/farmacologia , Hipocampo/citologia , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Cinética , Camundongos , Células Piramidais/metabolismo , Ratos
6.
Nat Commun ; 11(1): 2388, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404907

RESUMO

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson's disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.


Assuntos
Estimulação Encefálica Profunda/métodos , Levodopa/uso terapêutico , Transtornos Parkinsonianos/terapia , Somatostatina/metabolismo , Algoritmos , Animais , Antiparkinsonianos/uso terapêutico , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Motor/efeitos dos fármacos , Córtex Motor/metabolismo , Córtex Motor/fisiopatologia , Optogenética/métodos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Núcleo Subtalâmico/efeitos dos fármacos , Núcleo Subtalâmico/metabolismo , Núcleo Subtalâmico/fisiopatologia
7.
Nat Commun ; 11(1): 1567, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218435

RESUMO

Voltage-gated K+ channels function in macromolecular complexes with accessory subunits to regulate brain function. Here, we describe a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1)-dependent mechanism that regulates the association of the A-type K+ channel subunit Kv4.2 with its auxiliary subunit dipeptidyl peptidase 6 (DPP6), and thereby modulates neuronal excitability and cognitive flexibility. We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr607-Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex. We generated a novel mouse line harboring a knock-in Thr607 to Ala (Kv4.2TA) mutation that abolished dynamic Pin1 binding to Kv4.2. CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K+ current, and reduced neuronal excitability. Behaviorally, Kv4.2TA mice displayed normal initial learning but improved reversal learning in both Morris water maze and lever press paradigms. These findings reveal a Pin1-mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility.


Assuntos
Cognição , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Canais de Potássio Shal/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Células HEK293 , Humanos , Imidazóis/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Isomerismo , Aprendizagem , Camundongos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Ligação Proteica , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Piridinas/farmacologia , Convulsões/metabolismo , Convulsões/patologia , Canais de Potássio Shal/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Nat Commun ; 11(1): 1313, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152318

RESUMO

Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks-challenged by cognitive tasks-drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiopatologia , Eritropoetina/metabolismo , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Neurogênese , Plasticidade Neuronal , Animais , Diferenciação Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Eritropoetina/farmacologia , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Atividade Motora/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Condicionamento Físico Animal , Resistência Física/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Receptores da Eritropoetina/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
9.
Cell ; 180(4): 666-676.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32084339

RESUMO

The mystery of general anesthesia is that it specifically suppresses consciousness by disrupting feedback signaling in the brain, even when feedforward signaling and basic neuronal function are left relatively unchanged. The mechanism for such selectiveness is unknown. Here we show that three different anesthetics have the same disruptive influence on signaling along apical dendrites in cortical layer 5 pyramidal neurons in mice. We found that optogenetic depolarization of the distal apical dendrites caused robust spiking at the cell body under awake conditions that was blocked by anesthesia. Moreover, we found that blocking metabotropic glutamate and cholinergic receptors had the same effect on apical dendrite decoupling as anesthesia or inactivation of the higher-order thalamus. If feedback signaling occurs predominantly through apical dendrites, the cellular mechanism we found would explain not only how anesthesia selectively blocks this signaling but also why conscious perception depends on both cortico-cortical and thalamo-cortical connectivity.


Assuntos
Anestésicos Gerais/farmacologia , Córtex Cerebral/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Antagonistas Colinérgicos/farmacologia , Estado de Consciência , Dendritos/efeitos dos fármacos , Dendritos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Retroalimentação Fisiológica , Feminino , Masculino , Camundongos , Células Piramidais/fisiologia , Transmissão Sináptica , Tálamo/citologia , Tálamo/efeitos dos fármacos , Tálamo/fisiologia
10.
Biomed Pharmacother ; 124: 109850, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981945

RESUMO

Oxcarbazepine (OXC), a voltage-gated sodium channel blocker, is an antiepileptic medication and used for the bipolar disorders treatment. Some voltage-gated sodium channel blockers have been demonstrated to display strong neuroprotective properties in models of cerebral ischemia. However, neuroprotective effects and mechanisms of OXC have not yet been reported. Here, we investigated the protective effect of OXC and its mechanisms in the cornu ammonis 1 subfield (CA1) of gerbils subjected to 5 min of transient global cerebral ischemia (tGCI). tGCI led to death of most pyramidal neurons in CA1 at 5 days after ischemia. OXC (100 and 200 mg/kg) was intraperitoneally administered once at 30 min after tGCI. Treatment with 200 mg/kg, not 100 mg/kg OXC, significantly protected CA1 pyramidal neurons from tGCI-induced injury. OXC treatment significantly decreased superoxide anion production, 4-hydroxy-2-nonenal and 8-hydroxyguanine levels in ischemic CA1 pyramidal neurons. In addition, the treatment restored levels of superoxide dismutases, catalase, and glutathione peroxidase. Furthermore, the treatment distinctly inhibited tGCI-induced microglia activation and significantly reduced levels of pro-inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α). In particular, OXC treatment significantly enhanced expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream protein heme oxygenase-1 in ischemic CA1. The neuroprotective effects of OXC were abolished by brusatol (an inhibitor of Nrf2). Taken together, these results indicate that post-treatment of OXC can display neuroprotection against brain injuries following ischemic insults. This neuroprotection may be displayed by attenuation of oxidative stress and neuroinflammation, which can be mediated by activation of Nrf2 pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxcarbazepina/farmacologia , Animais , Isquemia Encefálica/fisiopatologia , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Catalase/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Gerbillinae , Glutationa Peroxidase/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Fármacos Neuroprotetores/administração & dosagem , Oxcarbazepina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
11.
Mar Drugs ; 18(1)2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31940961

RESUMO

Transient brain ischemia triggers selective neuronal death/loss, especially in vulnerable regions of the brain including the hippocampus. Laminarin, a polysaccharide originating from brown seaweed, has various pharmaceutical properties including an antioxidant function. To the best of our knowledge, few studies have been conducted on the protective effects of laminarin against ischemic injury induced by ischemic insults. In this study, we histopathologically investigated the neuroprotective effects of laminarin in the Cornu Ammonis 1 (CA1) field of the hippocampus, which is very vulnerable to ischemia-reperfusion injury, following transient forebrain ischemia (TFI) for five minutes in gerbils. The neuroprotective effect was examined by cresyl violet staining, Fluoro-Jade B histofluorescence staining and immunohistochemistry for neuronal-specific nuclear protein. Additionally, to study gliosis (glial changes), we performed immunohistochemistry for glial fibrillary acidic protein to examine astrocytes, and ionized calcium-binding adaptor molecule 1 to examine microglia. Furthermore, we examined alterations in pro-inflammatory M1 microglia by using double immunofluorescence. Pretreatment with 10 mg/kg laminarin failed to protect neurons in the hippocampal CA1 field and did not attenuate reactive gliosis in the field following TFI. In contrast, pretreatment with 50 or 100 mg/kg laminarin protected neurons, attenuated reactive gliosis and reduced pro-inflammatory M1 microglia in the CA1 field following TFI. Based on these results, we firmly propose that 50 mg/kg laminarin can be strategically applied to develop a preventative against injuries following cerebral ischemic insults.


Assuntos
Gliose/tratamento farmacológico , Glucanos/administração & dosagem , Glucanos/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Células Piramidais/efeitos dos fármacos , Animais , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Gerbillinae , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica
12.
Biochem Biophys Res Commun ; 522(4): 1059-1062, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31818459

RESUMO

Selectively activating (by optogenetics) parvalbumin-expressing (PV) interneurons induces GABA release onto CA1 pyramidal cells. Here we report that this release was attenuated by presynaptic mu opioid receptors (MORs) activation. On the other hand, conventional electric shock, presumably activating non-selectively presynaptic GABAergic terminals, also induced GABA release; however, this release showed relatively limited depression by MORs activation. The data suggest that MORs specifically inhibit GABA release from PV terminals and therefore, further support the idea that MORs contribute to homeostasis in CA1 neuro-circuit.


Assuntos
Região CA1 Hipocampal/citologia , Interneurônios/metabolismo , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Receptores Opioides mu/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Feminino , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Transgênicos , Células Piramidais/efeitos dos fármacos
13.
Int J Mol Sci ; 22(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383859

RESUMO

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson's disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Memória , Rotenona/administração & dosagem , Percepção Gustatória/efeitos dos fármacos , Administração Intranasal , Animais , Córtex Cerebral/citologia , Camundongos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Receptores de GABA-A/metabolismo , Percepção Gustatória/genética
14.
Neural Plast ; 2019: 4383258, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827497

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that regulates gene expression through poly(ADP)-ribosylation, resulting in the loosening of chromatin structure. PARP-1 enzymatic activity has been shown to be necessary for the expression of several genes required for memory formation and consolidation. Previously, we showed that nucleolar PARP-1 is significantly decreased in hippocampal pyramidal cells in Alzheimer's disease (AD). We proposed that the displacement of PARP-1 from the nucleolus results in downregulation of new rRNA expression and ribosome biogenesis, leading to cognitive impairment. To further investigate the relationship between nucleolar PARP-1 and memory impairment, we examined PARP-1 expression in the hippocampi of individuals with mild cognitive impairment (MCI) compared to control and AD cases. We used immunohistochemical techniques to examine the nucleolar distribution of PARP-1 in the Cornu Ammonis (CA region) of the hippocampus. PARP-1 positive cells were then scored for the presence or absence of PARP-1 in the nucleolus. We found a significant decrease of PARP-1 staining in the nucleolar compartment of hippocampal pyramidal cells in MCI compared with Control and AD. When the four CA (CA1-4) regions were considered separately, only the CA1 region showed significant differences in nucleolar PARP-1 with Control > AD > MCI cases. Categorization of nucleolar PARP-1 into "distinct" and "diffuse" groups suggest that most of the changes occur within the distinct group. In addition, measurements of the nucleolar diameter of nucleolar PARP-1 positive cells in CA2 and CA4 showed Control > MCI. Thus, MCI cases had a lower percentage of PARP-1 nucleolar positive cells in CA1 and smaller nucleolar diameters in CA2 and CA4, compared to Control. Our data suggest that disruption of nucleolar form and function is an early and important step in the progression of cognitive impairment.


Assuntos
Disfunção Cognitiva/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , Cognição/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo
15.
Neuroreport ; 30(18): 1316-1322, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31714483

RESUMO

Serotonin modulates cognitive processes and is related to various psychiatric disorders, including major depression. Administration of citalopram reduces the amplitude of auditory evoked potentials in depressed people and animal models, suggesting that 5-HT has an inhibitory role. Here, we characterize the modulation of excitatory post-synaptic currents by application of either 5-HT or agonists of 5-HT1A and 5-HT2 receptors, or by endogenous 5-HT evoked by citalopram on pyramidal neurons from layer II/III of rat auditory cortex. We found that application of 5-HT concentration-dependently reduces excitatory post-synaptic currents amplitude without changing the paired-pulse ratio, suggesting a post-synaptic modulation. We observed that selective agonists of 5-HT1A and 5-HT2 receptors [8-OH-DPAT (10 µM) and DOI (10 µM), respectively] mimic the effect of 5-HT on the excitatory post-synaptic currents. Effect of 5-HT was entirely blocked by co-application of the antagonists NAN-190 (1 µM) and ritanserin (200 nM). Similarly, citalopram application (1 µM) reduced the amplitude of the evoked excitatory post-synaptic currents. Reduction in the magnitude of the excitatory post-synaptic currents by endogenous 5-HT was interpolated in the dose-response curve elicited by exogenous 5-HT, yielding that citalopram raised the extracellular 5-HT concentration to 823 nM. Effect of citalopram was blocked by the previous application of NAN-190 but not ritanserin, indicating that citalopram reduces glutamatergic synaptic transmission via 5-HT1A receptors in layer II/III of the auditory cortex. These results suggest that the local activity of 5-HT contributes to decrease in the basal excitability of the auditory cortex for enhancing the detection of external relevant acoustic signals.


Assuntos
Córtex Auditivo/efeitos dos fármacos , Citalopram/farmacologia , Ácido Glutâmico/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Córtex Auditivo/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Piperazinas/farmacologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Ratos , Ratos Wistar
16.
Pharmacogenomics ; 20(17): 1199-1223, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31686592

RESUMO

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.


Assuntos
Discinesia Induzida por Medicamentos/genética , Estresse Oxidativo/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/genética , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Dopamina/genética , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/patologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/efeitos adversos , Fármacos Atuantes sobre Aminoácidos Excitatórios/uso terapêutico , Humanos , Neostriado/efeitos dos fármacos , Neostriado/patologia , Farmacogenética , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Receptores 5-HT2 de Serotonina/genética , Esquizofrenia/complicações , Esquizofrenia/genética , Esquizofrenia/patologia , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/patologia
17.
Neuroreport ; 30(17): 1197-1204, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568204

RESUMO

Ketamine is commonly used as a dissociative anesthetic with unique actions in the central nervous system. Previous studies have found that the thalamocortical systems play an important role in general anesthetics induced unconsciousness. Whether the voltage-gated sodium channels in the thalamocortical systems are the target of ketamine remain unclear. The present study used a whole-cell patch-clamp technique to observe the effects of ketamine on voltage-gated Na channels in thalamocortical pyramidal neurons. We found that IC50 of ketamine on Na currents in the primary somatosensory barrel cortex pyramidal neurons and the thalamus ventral posteromedial nucleus pyramidal neurons was 686.72 ± 39.92 and 842.65 ± 87.28 µM, respectively. Ketamine accelerated the Na channels inactivation and slowed inactivation of Na channels after recovery but did not affect the activation. We demonstrated the detailed suppression process of neural voltage-gated Na channels by ketamine on thalamocortical slice. This may provide a new insight into the mechanical explanation for the ketamine anesthesia.


Assuntos
Anestésicos Dissociativos/farmacologia , Ketamina/farmacologia , Córtex Somatossensorial/efeitos dos fármacos , Núcleos Ventrais do Tálamo/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Animais , Masculino , Técnicas de Cultura de Órgãos , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
PLoS One ; 14(10): e0223469, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618234

RESUMO

The goal of this study was to investigate the effects of acute cocaine injection or dopamine (DA) receptor antagonists on the medial prefrontal cortex (mPFC) gamma oscillations and their relationship to short term neuroadaptation that may mediate addiction. For this purpose, optogenetically evoked local field potentials (LFPs) in response to a brief 10 ms laser light pulse were recorded from 17 mice. D1-like receptor antagonist SCH 23390 or D2-like receptor antagonist sulpiride, or both, were administered either before or after cocaine. A Euclidian distance-based dendrogram classifier separated the 100 trials for each animal in disjoint clusters. When baseline and DA receptor antagonists trials were combined in a single trial, a minimum of 20% overlap occurred in some dendrogram clusters, which suggests a possible common, invariant, dynamic mechanism shared by both baseline and DA receptor antagonists data. The delay-embedding method of neural activity reconstruction was performed using the correlation time and mutual information to determine the lag/correlation time of LFPs and false nearest neighbors to determine the embedding dimension. We found that DA receptor antagonists applied before cocaine cancels out the effect of cocaine and leaves the lag time distributions at baseline values. On the other hand, cocaine applied after DA receptor antagonists shifts the lag time distributions to longer durations, i.e. increase the correlation time of LFPs. Fourier analysis showed that a reasonable accurate decomposition of the LFP data can be obtained with a relatively small (less than ten) Fourier coefficients.


Assuntos
Antagonistas de Dopamina/farmacologia , Potenciais Evocados , Optogenética , Algoritmos , Animais , Análise por Conglomerados , Potenciais Evocados/efeitos dos fármacos , Análise de Fourier , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Camundongos , Optogenética/métodos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo
19.
eNeuro ; 6(6)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31619450

RESUMO

Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PDs) that are nearly indistinguishable from spontaneously-occurring interictal spikes (IISs). By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (LEV; 40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced PD threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.


Assuntos
Potenciais de Ação/fisiologia , Região CA1 Hipocampal/fisiologia , Rede Nervosa/fisiologia , Optogenética , Células Piramidais/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Região CA1 Hipocampal/efeitos dos fármacos , Convulsivantes/farmacologia , Levetiracetam/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Rede Nervosa/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Células Piramidais/efeitos dos fármacos
20.
Sci Signal ; 12(603)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615899

RESUMO

KCC2 is a vital neuronal K+/Cl- cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007 We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+ ) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology.


Assuntos
Rede Nervosa/metabolismo , Células Piramidais/metabolismo , Simportadores/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/embriologia , Região CA3 Hipocampal/crescimento & desenvolvimento , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento , Potenciais da Membrana/efeitos dos fármacos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Técnicas de Patch-Clamp , Fosforilação , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Simportadores/genética , Ácido gama-Aminobutírico/farmacologia
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